Hair follicles (HFs) function as hubs for stem cells, immune cells, and commensal microbes, which must be tightly regulated during homeostasis and transient inflammation. Here we found that transmembrane endopeptidase ADAM10 expression in upper HFs was crucial for regulating the skin microbiota and protecting HFs and their stem cell niche from inflammatory destruction. Ablation of the ADAM10-Notch signaling axis impaired the innate epithelial barrier and enabled Corynebacterium species to predominate the microbiome. Dysbiosis triggered group 2 innate lymphoid cell-mediated inflammation in an interleukin-7 (IL-7) receptor-, S1P receptor 1-, and CCR6-dependent manner, leading to pyroptotic cell death of HFs and irreversible alopecia. Double-stranded RNA-induced ablation models indicated that the ADAM10-Notch signaling axis bolsters epithelial innate immunity by promoting β-defensin-6 expression downstream of type I interferon responses. Thus, ADAM10-Notch signaling axis-mediated regulation of host-microbial symbiosis crucially protects HFs from inflammatory destruction, which has implications for strategies to sustain tissue integrity during chronic inflammation.

毛囊 (HF) 是干细胞、免疫细胞和共生微生物的枢纽，在稳态和短暂炎症期间必须对其进行严格调节。在这里，我们发现上层 HF 中跨膜内肽酶 ADAM10 的表达对于调节皮肤微生物群和保护 HF 及其干细胞生态位免受炎症破坏至关重要。ADAM10-Notch 信号轴的消融损害了先天上皮屏障并启用了棒状杆菌微生物群中占主导地位的物种。生态失调以白细胞介素 7 (IL-7) 受体、S1P 受体 1 和 CCR6 依赖性方式触发了第 2 组先天性淋巴细胞介导的炎症，导致 HF 细胞焦亡和不可逆的脱发。双链 RNA 诱导的消融模型表明，ADAM10-Notch 信号轴通过促进 I 型干扰素反应下游的 β-defensin-6 表达来增强上皮先天免疫。因此，ADAM10-Notch 信号轴介导的宿主-微生物共生调节至关重要地保护 HF 免受炎症破坏，这对于在慢性炎症期间维持组织完整性的策略具有重要意义。